DESCRIPTION Both antigen-dependent and independent processes are thought to contribute to progressive renal allograft failure through pathways that may interrelate synergistically. Infiltrates of T lymphocytes and macrophages, common features of kidneys with chronic renal allograft dysfunction, are also seen in the remnant kidney undergoing progressive injury The overall objectives of this proposal are to investigate the role of cell mediated immunity in the development of renal injury induced by extensive renal ablation. The availability of inhibitors of T cell co-stimulatory signals provides us with novel and highly specific tools to elucidate the role of T cells and macrophages in the development of chronic progressive renal disease. The aim of this proposal is to study the effects of inhibition of the CD28-B7 and CD40-CD40L pathways to determine their respective contributions to the development of chronic progressive organ dysfunction in this model. In addition, we plan to study the contribution of the T cell co-stimulatory pathway to the development of renal injury in the context of pharmacological inhibition of the renin-angiotensin system once injury is established. We will test the hypothesis that blockade of the T cell co- stimulatory pathways provides renal protection in addition to that provided by blockade of the renin-angiotensin system. Better understanding of the role of immune mechanisms in this model of renal injury may ultimately lead to broader therapeutic options for patients with chronic progressive renal and other organ diseases in the future.